Genetic Drug Protects Heart Tissues from Oxidative Stress

Researchers have developed a method for preventing tissue damage following heart attack by using an adeno-associated virus vector to insert the gene that codes for the enzyme heme oxygenase, which generates antioxidants that protect cells under oxidative stress.

Investigators at Brigham and Women's Hospital (Boston, MA, USA) created a genetic drug by attaching the gene that codes heme oxidase (HO-1) to an adeno-associated virus vector. Heme oxygenase (HO) is a microsomal enzyme that catalyzes the oxidation of heme to the antioxidant molecules, biliverdin and carbon monoxide. HO consists of two homologous isozymes, an inducible HO-1 and a constitutively expressed HO-2. HO-1 is induced by a wide variety of stimuli including conditions of oxidative stress, inflammatory agents, transforming growth factor beta, and heat shock. The increase in expression of HO-1 is thought to be a cellular defense mechanism against oxidative stress since elevated HO could eventually generate more bilirubin, an antioxidant. The adeno-associated vector used to insert the gene has been shown to be safe for humans through its use in the treatment of hemophilia.


The investigators injected the drug into the heart, liver, and skeletal muscle of rats, and then five weeks later they restricted blood flow to the animals' organs by clamping key arteries for a period of one hour. They reported in the August 9, 2004, online edition of the Proceedings of the [U.S.] National Academy of Sciences that the treated animals showed a 65% decrease in tissue death compared to control animals. One month after treatment the control animals exhibited severe thinning of the heart wall and reduced heart function compared to the treated group. After four months, the controls still showed marked thinning of the heart wall, while the treated group showed virtually no evidence of damage.

"While drugs that can protect heart muscle are available, most patients barely make it to the hospital in time to take advantage of them,” said senior author Dr. Victor J. Dzau, now chancellor of health affairs at Duke University (Durham, NC, USA). "This smart gene therapy could be administered preemptively to high-risk patients months before they develop a heart attack to provide them with long-term protection from ischemic injury. The minute this gene is switched on following a loss of blood flow, levels of the therapeutic protein rise rapidly, providing near-complete protection.”




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